As reported by Sutherland et al., in "Cyclic AMP," Am. Rev. Biochem. 37, 149 (1968), cyclic adenosine monophosphate (C-AMP) has been established as an intracellular "second messenger," mediating many of the actions of a variety of different hormones. According to this theory, first messenger hormones, epinephrine and norepinephrine, influence adenyl cyclase contained at or within cell walls to form intracellulary, cyclic AMP from adenosine triphosphate upon receipt of the extra-cellular hormone signal. The formed cyclic AMP in turn functions as a second messenger and stimulates intracellular functions particularly to the target cells of the hormone. Cyclic AMP has thus been shown to "activate" protein kinases, which in turn produce physiological effects such as muscle contraction, glycogenolysis, steroidogenesis and lipolysis.
Cyclic AMP is degraded, however, in vivo by phosphodiesterase enzymes, which catalyze hydrolysis of the cyclic purine nucleotide to 5'-adenosine monophosphate with a consequent loss of function. It has accordingly been suggested that substituted cyclic AMP analogs which are more resistant to phosphodiesterase degradation than the naturally occurring cyclic nucleotide might be administered in aid of lagging cellular processes. Synthetic production of such compounds, however, is quite costly. It would be advantageous, therefore, to enhance the beneficial effects of naturally produced cyclic AMP by administering compounds which are capable of inhibiting the undesirable effects of phosphodiesterase enzymes.
Sutherland et al., in Circulation 37, 279 (1968), suggest that the pharmacological effects of theophylline, which has the structure ##STR2## are the result of its ability to inhibit the action of phosphodiesterase enzymes. Theophylline has thus been employed in lieu of the adenyl cyclase-stimulating hormones, epinephrine and norepinephrine, as a heart stimulant following cardiac arrest and in refractory asthma cases as a bronchial dilator. Theophylline, however, does not selectively inhibit phosphodiesterase, but rather gives general stimulation to the central nervous system. Accordingly, the use of theophylline can make the recipient nervous and irritable and can also create cardiovasular effects, i.e., rapid beating. By the same token, theophylline is not as potent as a phosphodiesterase inhibitor as is desired and consequently has to be used in larger quantities, which, of course, can further the undesirable effects enumerated above.
As indicated in the application of Darrell E. O'Brien et al., Ser. No. 206,538, entitled "3,5,7-trisubstituted pyrazolo[1,5a] pyrimidines," assigned to the same assignee as this application, various 5,7 -dialkyl- and 5-alkyl-3,7-disubstitutedpyrazolo[1,5a] pyrimidines have been found to possess phosphodiesterase inhibition properties. Further evaluation of such compounds has shown that 3-bromo-5,7-dimethylpyrazolo[1,5a]pyrimidine not only is significantly more active than theophylline against various phosphodiesterase enzymes, but also has the ability to produce a positive inotropic effect in an anesthetized dog, which has accordingly led to the investigation of additional derivatives of such pyrazolo[1,5a] pyrimidine ring system, including 6-carbethoxy-pyrazolo[1,5a] pyrimidines set forth in the application of Darrell E. O'Brien et al., entitled "6-carbethoxy-3,7-disubstitutedpyrazolo[1,5a]pyrimidines" and assigned to the same assignee as this application, and the triazolo[1,5a]pyrimidine ring system of this invention.